Alzheimer's disease (AD) is the most common form of neurodegeneration and has become a major healthcare issue with the aging population in the United States.
As people advance past the age of 65, the risk for developing Alzheimer's disease increases. As the leading cause of dementia, clinical AD symptomology includes both cognitive impairment and deficits in memory function.
AD patients exhibit heavy senile plaque burden in the cerebral cortex, verified by post mortem histopathological examination. Interestingly, despite the development and presence of senile plaques in elderly persons with normal cognitive function, the severity of neurofibrillary tangles (NFT) and senile plaque deposition purportedly correlates with a loss of cognitive function and neuronal circuitry deterioration. Mature senile plaques consist of intracellular neurofibrillary tangles derived from filaments of hyperphosphorylated tau proteins, and extracellular β-amyloid peptides derived from enzymatic processing of amyloid precursor protein.
Amyloidosis is characterized by the progressive, bulk accumulation of insoluble fibrillary proteins in the patient tissue, leading ultimately to morbidity. Deposition of amyloid occurs via aggregation of the fibrillary proteins, followed by further combination or aggregation thereof. With respect to AD, accumulation of aggregates of amyloid peptides Aβ40 and Aβ42 are the major peptides found in senile plaque and cerebrovascular deposits in patents (see Xia, et al., J. Proc. Natl. Acad. Sci. USA, 97: 9299 (2000) and Hardy, et al, Science 2002, 297, 353). Prevention of the deposition of these peptide fragments, which are derived from amyloid precursor proteins, continues to be a primary therapeutic research goal. Due to the central role of γ-secretase in the generation of the Aβ peptides via cleavage of amyloid precursor protein (APP), inhibition of γ-secretase has been identified as an important target in the discovery of novel AD treatments (see, for example, Ziani-Cherif, et al, Curr. Pharm. Design 2006, 12, 4313-4335; Evin, et al, CNS Drugs 2006, 20, 351-372; and Lahiri, et al., Drug Dev. Res. 2002, 56, 267-281).
Diagnosis of AD has been traditionally performed via post-mortem tissue studies, brain biopsies or clinical evaluation [see, for example, McKhann, et al., Neurology, 34: 939 (1984) and Khachaturian, Arch. Neurol., 42: 1097 (1985)]. AD is clinically characterized by the presence of neurotic plaques (NP), neurofibrillary tangles (NFT) and neuronal loss (see. Mann, Mech. Aging Dev. 31: 213 (1985). Neurotic plaques are a ubiquitous aspect of the disease (Mann et al., J. Neurol. Sci., 89: 169), the assessment of which must be performed in postmortem studies.
Unfortunately, at the stage of presentation of symptoms in the clinic, the patients have developed significant amyloid deposition in the neurological tissue. More recently, earlier diagnosis has been the subject of research efforts aimed at immunoassay techniques, genetic testing and radiological imaging technologies.
Discovery of point mutations in amyloid precursor protein (APP) in several rare families with an autosomal dominant form of AD provided evidence that abnormalities in Aβ metabolism are necessary and sufficient for the development of AD (see, for example, Hardy, Nature Genetics, 1: 233 (1992); and Hardy, et al., Science, 256: 184 (1992). Heterogeneous evidence of AD has also been demonstrated via analysis of a large number of families of AD (see, St. George-Hyslop, et al., Nature, 347: 194 (1990). In particular, a gene on chromosome 14 has been identified which may account for up to 70% of early-onset AD, as mutation of which may significantly increase production of the Aβ peptide (Sherrington, et al., Nature, 375: 754 (1995)).
Immunoassay methods have been developed for detecting the presence of neurochemical markers in AD patients and to detect an AD related amyloid protein in cerebral spinal fluid, however such methods have not proven reliable in all patients and require invasive procedures such as a spinal tap.
Monoclonal antibodies and radiolabeled peptides have been used as probes for imaging of Aβ, however these macromolecular structures provide inherently poor brain penetration (see, for example, Majocha, et al., J. Nucl. Med., 33: 2184 (1992)). Additionally, the peptide probes may lack specificity for AD as they tend to react with diffuse plaques.
In addition to AD, amyloid deposits have also been associated with other diseases such as, for example, glaucoma, Mediterranean fever, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, hereditary cerebral hemorrhage, Muckle-Wells syndrome, Down's syndrome, Gerstmann-Straussler-Scheinker syndrome, Creutzfeldt-Jacob disease, scrapie, kuru, Islets of Langerhans, isolated atrial amyloid, medullary carcinoma of the thyroid and inclusion body myositis to name a few.
Though treatments exist, efficacy is observed in a palliative sense rather than halting the progression of AD, providing the patient with only a temporarily improved quality of life. It has been reported that delaying AD onset by five years is sufficient to reduce the number of AD cases by half. To this end, there are a number of therapies that delay full onset AD. Typically, clinicians prescribe cholinesterase inhibitors to cognitively impaired patients to help delay AD progression. Rivastigmine, a therapeutic treatment for both AD and Parkinson's disease patients, inhibits both acetylcholinesterase and butyrylcholinesterase, preventing the breakdown of acetyl- and butyrylcholine. Galantamine, a naturally derived acetylcholinesterase inhibitor, increases nicotinic cholinergic receptors' release of acetylcholine into the brain. Finally, the acetylcholinesterase inhibitor Aricept slows progression of AD in patients by inhibiting acetylcholinesterase and thus increasing cortical acetylcholine. In a recent clinical trial, Aricept slowed AD progression in patients, but the therapeutic effects disappeared after 36 months. The effect of treating AD patients with a therapeutic combination of both Aricept and memantine caused an increased cognitive function in those AD patients relative to those treated only with Aricept. Despite the utility of cholinesterase inhibitors, the current array of AD therapeutics merely serves to delay full-onset AD by approximately two to three years, after which they are therapeutically ineffective in inhibiting cognitive decline.
Neurological imaging of AD has seen the emergence of imaging tracers that appear to confirm the presence of AD based on plaque and fibril mediated tracer uptake and, subsequently, are currently undergoing extensive clinical examination. Many of these tracers contain chemotypes that derive from fluorescent dyes or Aβ peptides. For example, increased uptake and binding of the napthylaniline derivative 18F-FDDNP in living brains correlates well with the presence of AD when compared to cognitively functional normals of similar age (High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malonitrile ([18F]FDDNP) Ready for Animal or Human Administration, Liu, J., et al., Molecular Imaging and Biology, 2007. 9: p. 6-16). The thioflavin derived AD imaging agent, 11C-PIB, shows enhanced uptake in frontotemporal and hippocampal brain regions in AD patients compared to healthy age-matched normals.
Several other chemotypes have been identified as plaque imaging agents. These chemotypes are radiolabeled for use as PET or SPECT imaging agents. The scaffolds include compounds derived from benzothiazoles, naphthyl amines, flavones, aurones, isoindoles and styrenes. The chemotypes bind to plaques and fibrils with varying affinities and differing binding sites (see, for example, US 2007/0258887). Disclosed in this application are additional scaffolds that bind to AD plaques and fibrils.
A number of medical diagnostic procedures, including PET and SPECT utilize radiolabeled compounds, are well known in the art. PET and SPECT are very sensitive techniques and require small quantities of radiolabeled compounds, called tracers. The labeled compounds are transported, accumulated and converted in vivo in exactly the same way as the corresponding non-radioactively compound. Tracers, or probes, can be radiolabeled with a radionuclide useful for PET imaging, such as 11C, 13N, 15O, 18F, 64Cu and 124I, or with a radionuclide useful for SPECT imaging, such as 99Tc, 77Br, 61Cu, 153Gd, 123I, 125I, 131I and 32P.
PET creates images based on the distribution of molecular imaging tracers carrying positron-emitting isotopes in the tissue of the patient. The PET method has the potential to detect malfunction on a cellular level in the investigated tissues or organs. PET has been used in clinical oncology, such as for the imaging of tumors and metastases, and has been used for diagnosis of certain brain diseases, as well as mapping brain and heart function. Similarly, SPECT can be used to complement any gamma imaging study, where a true 3D representation can be helpful, for example, imaging tumor, infection (leukocyte), thyroid or bones.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.